The Tumor-Host Interactions Program (THI) at the University of Colorado Cancer Center has awarded four CU Cancer Center researchers $30,000 each to gain preliminary data using the Multiplex Ion Beam Imager (MIBI) housed in the cancer center’s Human Immune Monitoring Shared Resource (HIMSR) to support a competitive national grant proposal. The selected researchers are expected to submit a national competitive grant proposal within six months of completing their THI-MIBI pilot studies.
The MIBI is a tissue-imaging instrument that allows researchers to examine up to 40 different proteins at a time on one piece of tissue. “This is really important because scientists often need to look at many different markers at one time to get a complete picture of the cells’ types and function of those cells in the tumor,” says CU Cancer Center member Kimberly Jordan, PhD, assistant director of the HIMSR. “Because it can take such a wide ‘view’ of what is happening in tumors, the MIBI can help identify biomarkers of disease status and potential therapeutic targets, and help answer mechanistic questions about why some patients do well with certain treatments.”
David Woods, PhD, Kasey Couts, PhD, Alisa Lee-Sherick, MD, and Traci Lyons, PhD, are the recipients of the 2022 THI-MIBI Pilot Grants.
Exploring ectoenzymes
In his pilot project, Woods will use the MIBI on a research project aimed at understanding why some metastatic melanomas fail to respond to immunotherapy. The resistance, he theorizes, has to do with a population of T cells co-expressing the ectoenzymes CD38 and CD39, which suppress the anti-tumor immune response.
“We extend our appreciation for this award,” Woods says. “These funds and the support of the HIMSR core will help us develop a high-parameter, issue-imaging panel to investigate the roles of adenosine signaling and immune populations in tumors. Our goal is to investigate adenosine signaling as biomarkers of patient response to immunotherapies and generate rationale for new therapeutic targets. We also believe this panel will serve as a tool for other researchers investigating cancer and other diseases.”
Finding new treatment for ER-positive breast cancer patients
Lyons will use her THI-MIBI Pilot Grant to continue her research on semaphorin 7a, a molecule that appears to drive metastasis of breast cancers. Her lab has discovered that semaphorin 7a may be particularly important in estrogen receptor (ER) positive breast cancer.
“This proposal represents a large team effort toward understanding mechanisms of immunosuppression in the tumor microenvironment (TME) of breast cancers,” Lyons says. “For years I, along with my colleagues Virginia Borges, MD, Jennifer Richer, PhD, and Jill Slansky, PhD, have had a strong interest in this topic. Thanks to the advancement in technology that the MIBI provides, alongside a novel tissue microarray provided in kind by a longstanding collaborator, Dr. Andrew Nelson at the University of Minnesota Masonic Cancer Center, this award will help in the fight against breast cancer by identifying elements of the TME that could either be directly targeted or utilized as predictive biomarkers for targeted therapies.”
Investigating rare melanomas
In her pilot project, Couts will investigate why acral melanomas — melanomas that form on the palms, soles of the feet, and under fingernails or toenails — and mucosal melanomas, which invade mucosal tissue in the body including the nasal cavity and the lining of the sinuses and mouth, do not respond to immunotherapy as well as sun-related melanomas.
“I am incredibly excited to be selected for this award, which will use cutting-edge technology to characterize the immune landscape in the rare, non-sun-related acral and mucosal subtypes of malignant melanoma,” says Couts, co-director of the CU Center for Rare Melanomas.“These types of melanomas spread more aggressively and do not respond well to immunotherapy treatments. The data generated by this grant will provide critical clues about the role of tumor immunity in metastasis and immunotherapy resistance, ultimately guiding us as we develop new treatment strategies for these particularly deadly forms of melanoma.”
Targeting macrophages
Lee-Sherick’s pilot project, “Reversing Immune Suppression by Tumor Associated Macrophages in Rhabdomyosarcoma,” looks at new treatment options for rhabdomyosarcoma, the most common soft-tissue cancer in children.
“Despite various treatment options including chemotherapy and radiotherapy, cure rates for pediatric rhabdomyosarcoma patients with relapsed and metastatic disease continues to be dismal,” Lee-Sherick says. “Recently, many cancers have benefitted from immunotherapies — treatments that are developed to train cancer-killing T cells to attack and destroy cancer cells — however, immunotherapies have not been effective in rhabdomyosarcoma, likely because of the presence of non-cancer cells within the tumor called tumor-associated macrophages, which suppress the T cells’ ability to recognize and kill cancer cells.”
In her study, Lee-Sherick is looking at ways to stop the tumor-associated macrophages from carrying out a process called “efferocytosis,” in which macrophages eat up dead and wounded tissue during the healing phase after infection or injury. As cancer cells seem to be co-opting this mechanism to avoid being recognized by T cells, she says, using medication to block efferocytosis can help immunotherapies work more effectively.
“Our goal is to develop out-of-the-box macrophage-based therapies for patients with solid tumors, which ultimately could decrease the amount of high-dose chemotherapy and radiotherapy needed to induce remission or cure, and generate long-term anti-tumor immunity, thereby improving patient outcomes,” Lee-Sherick says. “Though we focus on rhabdomyosarcoma in this proposal, the ideas presented in this project are applicable to a multitude of other cancer types.”
